Management of hypersensitivity to platinum- and taxane-based chemotherapy: cepo review and clinical recommendations.

BACKGROUND: Although antineoplastic agents are critical in the treatment of cancer, they can potentially cause hypersensitivity reactions that can have serious consequences. When such a reaction occurs, clinicians can either continue the treatment, at the risk of causing a severe or a potentially fatal anaphylactic reaction, or stop the treatment, although it might be the only one available. The objective of the present work was to evaluate the effectiveness of methods used to prevent and treat hypersensitivity reactions to platinum- or taxane-based chemotherapy and to develop evidence-based recommendations. METHODS: The scientific literature published to December 2013, inclusive, was reviewed. RESULTS: Premedication with antihistamines, H2 blockers, and corticosteroids is not effective in preventing hypersensitivity reactions to platinum salts. However, premedication significantly reduces the incidence of hypersensitivity to taxanes. A skin test can generally be performed to screen for patients at risk of developing a severe reaction to platinum salts in the presence of grade 1 or 2 reactions, but skin testing does not appear to be useful for taxanes. A desensitization protocol allows for re-administration of either platinum- or taxane-based chemotherapy to some patients without causing severe hypersensitivity reactions. CONCLUSIONS: Several strategies such as premedication, skin testing, and desensitization protocols are available to potentially allow for administration of platinum- or taxane-based chemotherapy to patients who have had a hypersensitivity reaction and for whom no other treatment options are available. Considering the available evidence, the Comité de l'évolution des pratiques en oncologie made recommendations for clinical practice in Quebec.

Endothelin-B receptor-dependent modulation of the pressor and prostacyclin-releasing properties of dynamically converted big endothelin-1 in the anesthetized rabbit.

Big endothelin-1 (ET-1) injected systemically in vivo induces a long-lasting pressor response, in contrast to its active metabolite ET-1, which alters in a biphasic fashion the mean arterial pressure (MAP) of the anesthetized rabbit. In this study we investigated the effect of selective ETA or ETB receptor blockade on the pressor response and increase in plasma prostacyclin (PGI2) levels (determined by RIA) induced by big ET-1 in the anesthetized rabbit. Pretreatment (5 min) of the rabbit with the ETB receptor antagonist BQ-788 (0.25 mg/kg) potentiated the ET-1 (1 nmol/kg) and, interestingly, big ET-1 (0.5 nmol/kg) induced pressor responses. The selective ETA receptor antagonist BQ-123 (1 mg/kg) significantly reduced the big ET-1 (0.5 and 3 nmol/kg) pressor responses. Big ET-1 (3 nmol/kg) injected i.v. induced an increase in plasma PGI2 levels in contrast to intra-arterial (i.a.) administration. This increase was prevented by BQ-123 (1 mg/kg) but not by BQ-788 (0.25 nmol/kg). Furthermore, in the presence of BQ-788, i.a. administration of big ET-1 (3 nmol/kg) induced a significant release of PGI2. These results show that vasodilator ETB receptors may be activated after conversion of big ET-1 to its active metabolite. Furthermore, after pulmonary conversion of big ET-1, ETA receptors may be responsible for the release of vasodilator and anti-aggregatory prostacyclin, which modulates the big ET-1-induced responses in the rabbit.

ET(B) receptor and nitric oxide synthase blockade induce BQ-123-sensitive pressor effects in the rabbit.

Endothelin-1 (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is significantly reduced by the selective ET(A) receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ET(B) antagonist BQ-788 (0.25 mg/kg) induces a pressor response abolished by BQ-123 (1 mg/kg). Concomitant to the increase in mean arterial pressure, BQ-788 induces a significant increase in plasma levels of endothelin-1 and its precursor big endothelin-1. The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is reduced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the administration of BQ-788 in the presence of L-NAME induced a further increase in arterial blood pressure. The duration of the pressor response to L-NAME is also significantly reduced by an endothelin-converting enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-1 but not endothelin-1. Our results illustrate that blockade of either nitric oxide synthase or ET(B) receptors triggers a raise in plasma levels of endothelin-1 or its precursor. These later moieties are suggested to be significantly involved, through the activation of ET(A) receptors, in the pressor effects of L-NAME and BQ-788 in the anesthetized rabbit.

[Professional marginalization and affective illness (a case study).]. / Désinsertion professionnelle et maladies affectives (étude de cas).

The authors, a psychiatrist and a psychologist, provide an overview of how little understanding and research exist concerning the readaptation and professional réintégration of the mentally ill. The subject matter highlights the specific problems experienced by people plagued by emotional illnesses. The study also presents a case history which illustrates how "professional withdrawal" takes place for these people, in other words how their career is interrupted and/or how they experience the aftermath of the loss of a stable job. In conclusion, the authors recommend that a new branch of psychiatry dealing with work be opened, that a new professional role in psychiatry be established following what already exists at Louis-H Lafontaine Hospital and, eventually, that changes be made to the status of mentally ill patients and to their being labeled handicapped. The authors also recommend that research be undertaken on emotionally ill people who are victims of professional withdrawal, in order to properly assess the seriousness of the problem.

A comparative double-blind controlled study of trimipramine and amitriptyline in major depression: lack of correlation with 5-hydroxytryptamine reuptake blockade.

Thirty-four hospitalized patients with major depression were enrolled in a 3-week double-blind parallel comparative study of trimipramine and amitriptyline. Following a 1-week washout period, patients randomly received one of the two drugs up to 100 mg twice daily on a fixed increment dosage schedule. Both treatments produced a rapid significant clinical improvement that occurred in a predominantly linear fashion. The pattern of improvement was very similar with both drugs. There was no significant correlation between plasma levels of trimipramine and desmethyl-trimipramine and clinical improvement. A negative correlation between amitriptyline plasma levels and clinical improvement was found, whereas a positive correlation occurred with the nortriptyline levels. Amitriptyline, and to a lesser extent trimipramine, prolonged intracardiac conduction. In the amitriptyline group only, this effect was accompanied by significant increases of heart rate and blood pressure. Platelet serotonin content was decreased by 57% by the amitriptyline treatment but remained unchanged in the trimipramine group. This finding constitutes the first clinical evidence that trimipramine does not exert its antidepressant effect through 5-hydroxytryptamine reuptake blockade. It is proposed that neuronal sensitization to 5-hydroxytryptamine might mediate the therapeutic effect of tricyclic antidepressant drugs.

Acetate metabolism and bicarbonate generation during hemodialysis: 10 years of observation.

The capacity of chronically hemodialyzed patients to metabolize acetate during conventional hemodialysis was evaluated using a retrospective study in 219 patients dialyzed for up to ten years under similar dialysis conditions. For each patient, and using all available data, a regression line relating the changes of plasma total CO2 during dialysis as a function of the pre-dialysis value was calculated. The intercept of this function indicates the plasma concentration where the losses of bicarbonate in the dialysate is matched by the generation of bicarbonate arising from the metabolism of acetate. This value therefore represents an individual index of the capacity of each patient to metabolize acetate. A value for this index smaller than 18.0 mM was considered abnormal. It was shown that around 10% of chronically hemodialyzed patients are clearly unable to metabolize acetate optimally. This defect is not related to the duration of dialysis, body weight or quality of hemodialysis treatments but is strongly related to sex, 19 of the 22 "acetate intolerant" patients being women. In a prospective study, all the 60 patients of the same population undergoing active dialysis were studied, and this index identified 12 abnormal (11 women, 1 man) patients and 48 normal patients. Plasma acetate measured at the end their dialysis treatments were significantly higher in abnormal than in normal patients. It is concluded: that this index is useful to identify the patients unable to metabolize acetate optimally; that only around 10% of hemodialyzed patients present a severe problem when dialyzed against acetate and should be dialyzed against bicarbonate; that dialysis against acetate does not fully correct the metabolic acidosis even in "normal" patients.

High incidence of multisystemic reactions to zimeldine.

Forty-five patients suffering from a major depression were administered zimeldine, amitriptyline or placebo (15 patients in each group) in a double-blind controlled study. In the zimeldine group, seven of the 14 patients treated for more than one week presented a toxic syndrome consisting in a severe prostration, fever, myalgias and arthralgias. In all patients presenting this syndrome, laboratory analyses revealed an elevation of alkaline phosphatase and of aspartate and alanine aminotransferases and a decrease in white blood cell and platelet counts. Three patients presented a mild proteinuria and hematuria. Although an immunological mechanism cannot be ruled out, several characteristics of this reaction suggest the formation of a metabolite of zimeldine with direct cellular toxicity. The relatively high starting dose of 200 mg/day of zimeldine administered in the present study and the increment to 300 mg/day after only seven days might have contributed to the high incidence of toxic reactions observed.

Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system.

Preliminary reports suggested that the addition of lithium carbonate to the regimen of patients treated with, but not responding to, a tricyclic antidepressant (TCA) drug can induce a rapid alleviation of depression. We examined the effect of lithium carbonate addition in 39 patients with unipolar depression whose conditions were not improved by at least three weeks' TCA drug administration. In 30 of 42 observations, lithium carbonate brought about a greater than 50% improvement within 48 hours. In a second study, the effects of lithium carbonate addition were compared in five amitriptyline hydrochloride-pretreated and five placebo-pretreated patients who showed no improvement after a three-week treatment. All five patients receiving amitriptyline showed a greater than 50% improvement 48 hours after lithium carbonate addition, whereas only one patient in the placebo group showed a marked response. In a third study the effect of lithium carbonate withdrawal was studied in nine TCA-resistant patients who had shown a marked improvement 48 hours after lithium addition. Only five of these patients had a relapse five days after lithium discontinuation. Since animal studies have shown that TCA drugs sensitize forebrain neurons to serotonin and that lithium enhances the activity of serotonin-containing neurons, we propose that the antidepressant effect of lithium addition in TCA-resistant patients might be mediated by enhancing serotonin neurotransmission.

Computer system for a hospital microbiology laboratory.

An online computer system has been developed for a university hospital laboratory in microbiology that processes more than 125,000 specimens yearly. The system performs activities such as the printing of reports, fiscal and administrative tasks, quality control of data and technics, epidemiologic assistance, germ identification, and teaching and research in the different subspecialties of microbiology. Features of interest are smooth sequential transmission of clinical microbiologic test results from the laboratory to medical records, instantaneous display of all results for as long as 16 months, and updating of patient status, room number, and attending physician before the printing of reports. All data stored in the computer-file can be retrieved by any data item or combination of such. The reports are normally produced in the laboratory area by a teleprinter or by batch at night in case of mechanical failure of the terminal. If the system breaks down, the manually completed request forms can be sent to medical records. Programs were written in COBOL and ASSEMBLY languages.